PROJECT SUMMARY: This proposal for a program project grant (PPG) seeks to understand the mechanism of action of the novel pro- longevity hormone FGF21 by assembling a diverse and complementary group of investigators at Yale University and UT Southwestern. Fibroblast growth factor 21 (FGF21) is a member of the endocrine FGF subfamily that acts through a cell surface receptor composed of FGF receptors in complex with the obligate co- receptor ?Klotho. FGF21 is a unique metabolic hormone as it is secreted in blood from liver in response to starvation and nutrient deprivation to stimulate fatty acid oxidation and to maintain energy balance. Recent studies from our PPG team have demonstrated that overexpression of FGF21 in mice extends lifespan, improves insulin-sensitivity and may promote immune function. Based on these data, the central hypothesis of this program project is that FGF21 is a key driver of CNS-adipose tissue-immune system interactions that coordinately promote a prolongevity molecular program. Overall objective of this project is to elucidate the molecular mechanisms underlying FGF21's anti-aging effects and to leverage these insights towards inhibiting aging-related chronic diseases. Given the diverse backgrounds and skills of the research team, we can use state-of-the-art mouse models and methodology to assess the effects of FGF21 on multiple organ systems at different levels ranging from the molecular to the behavioral. We propose four projects to pursue the aims of this PPG: Project 1 under the leadership of Drs. Steven Kliewer and David Mangelsdorf will investigate the impact of FGF21 on growth hormone action, healthspan and lifespan. Project 2 under the leadership of Dr. Vishwa Deep Dixit will study the impact of FGF21-mediated immune-metabolic interactions on immune- senescence. The project 3 will be headed by Dr. Philipp Scherer to investigate the Impact of FGF21- adiponectin-ceramide axis on aging and Project 4 under the leadership of Dr. Tamas Horvath will study the impact of FGF21 on CNS and hypothalamic control of aging. The Core A will facilitate communications between projects and provide support for data analyses and Core B will provide centralized facility for analysis of aging and healthspan in mice. The PPG team will explore the novel hypothesis that FGF21 acts through multiple tissues to increase healthspan and lifespan.